The invention relates to a process for the preparation of hydroxytyrosol (3,4-dihydroxyphenylethanol).
Hydroxytyrosol is an effective antioxidant and has aroused great interest in recent years on account of its positive effects for health. Hydroxytyrosol is an active component of the Mediterranean diet. The European Food Safety Authority (EFSA) has verified polyphenols from olives as having a positive Health Claim, with a daily hydroxytyrosol dose of at least 5 mg being recommended. An antiinflammatory effect of hydroxytyrosol has also been described. Moreover, there are studies which show that hydroxytyrosol in vitro has antimicrobial properties against pathogens of the respiratory tract and of the gastrointestinal tract, such as against some strains of the genus Vibrio, Salmonella or Staphylococcus and that the dosage used can definitely compete with those of antibiotics, e.g. ampicillin. Moreover, the substance is attributed a neuroprotective and an anti-proliferative and pro-apoptotic effect. These properties make hydroxytyrosol a very interesting and much researched substance which is used in pharmaceuticals, food supplements, functional foods and also in cosmetics.
Hydroxytyrosol which has hitherto been available in the market originates for the large part from olives, olive leaves or wastewater which is produced during the production of olive oil and is supplied in the form of an extract. The proportion of hydroxytyrosol in these products is very small in most cases. Examples thereof are HIDROX™ with a hydroxytyrosol content below 12%, or OPEXTAN™ which contains about 4.5% hydroxytyrosol.
Besides the isolation of natural hydroxytyrosol from olives, numerous processes are described for preparing this substance synthetically. For example, WO 2008/107109 describes a process for the preparation, by reduction, of 4-(chloroacetyl)-1,2-dihydroxybenzene (4-(chloroacetyl)catechol) with the help of catalysts such as palladium/carbon. However, the preparation of the starting compound 4-(chloroacetyl)catechol requires high temperatures and long reaction times.
WO 2007/009590 A1 describes a process for the preparation of hydroxytyrosol via 3,4-dihydroxymandelic acid, which is hydrogenated by metal catalysts such as palladium/carbon to give 3,4-dihydroxyphenylacetic acid. Subsequently, the reduction to hydroxytyrosol takes place. According to the examples, the hydroxytyrosol obtained has purities between 67.9% and 93.8%. Apart from one example, which describes a product with a purity of 98% without stating the pure yield by recrystallization, the precursor obtained from 3,4-dihydroxymandelic acid ester, methyl 3,4-dihydroxyphenyl acetate, is described as product with purities between 51.2% and 83.5%.
The abstract for KR 2007 038702 A describes a synthesis via styrene oxide derivatives. The starting substance is hydrogenated in the presence of a precious metal catalyst such as palladium on activated carbon. Epoxides are unacceptable as regards a mutagenic or carcinogenic effect, meaning that traces in the end product are problematic for use in the food sector.
In the specified hydrogenation reaction, esters or acid analogs of hydroxytyrosol are reduced. Disadvantageously, precious metal catalysts or toxic catalysts such as nickel are required for this purpose.
WO 2008/110908 A1 describes a process starting from tyrosol. In the process, firstly the hydroxyethyl group is protected by means of different reagents, and then a second hydroxy group is inserted into the aromatic ring in the hydroxyethyl-protected tyrosol derivatives using derivatives of iodobenzoic acid. Both the starting material tyrosol and the oxidizing agents are very expensive compounds. The reaction is complex on account of the many feed materials. There are no details relating to the purity of the hydroxytyrosols obtained by the different processes.
WO 2009/153374 describes a preparation process starting from safrole. Both safrole and the HMPT used in the reaction are carcinogenic, meaning that this process is unsuitable for producing food supplements on account of the possible impurities.
WO 2012/003625 describes the preparation of hydroxytyrosol by ozonolysis of eugenol at low temperature and subsequent reduction of the resulting product. The demethylation then takes place with the help of a Lewis acid and a mercaptan. The low-temperature ozonolysis is an expensive reaction step in which secondary reactions such as oxidation of the phenolic group cannot be excluded. The demethylation with the help of extremely foul-smelling substances such as mercaptans, which moreover is not easy, makes the preparation of products for use as food supplements difficult. Both reaction steps evidently produce contaminated products, which are described as red oil.
WO 2012/006783 A1 describes the preparation of hydroxytyrosol starting from low cost pyrocatechol which, following protection of the phenolic groups, is halogenated. The halogenated protected pyrocatechol is then reacted with magnesium to give the corresponding Grignard compound, which is reacted with ethylene oxide in order to introduce the hydroxyethyl group into the aromatic ring. The demethylation takes place in turn with the help of ethanethiol (ethyl mercaptan) aluminum chloride or hydrogenolysis of benzyl ethers with the help of Pd/C and H2.
For all three described processes there is considerable purification complexity for each of the three stages. Moreover, the ethoxylation takes place with a considerable excess of ethylene oxide; a formation of oligomeric glycol units is therefore probable. Depending on the protective group, the demethylation takes place by Lewis acid and ethylmercaptan, with the problems already described, or by hydrogenolysis. The yields of hydroxytyrosol are 32% to 70% in the three described processes. The products obtained are yellow to red oils, which suggests considerable impurities. Possible impurities due to traces of carcinogenic ethylene oxide are problematic for use in the food supplement sector.
The abstract for CN102344344 describes a process in which 3,4-dialkoxyphenylacetic acid alkyl ester (alkyl C1-C5 and benzyl) are reduced and demethylated in one step with the help of sodium in alcohols. The advantage of the process is the one-pot reaction, although it is known that the cleavage of aryl ethers with the help of sodium in alcohols is associated with considerable byproduct formation since a cleavage of the aryl ether between oxygen and aromatic ring also arises. In the examples, the yield is at most 50%. In all of the examples, purification by column chromatography is required.
The abstract for CN101891595 describes a very complex four-stage process for the preparation of hydroxytyrosol with unknown purification complexity and impurities.
The reductive cleavage of 2,2-dialkyl-1,3-benzodioxole derivatives with the help of diisobutylaluminum hydride is described by G. Schill et al.; Chem. Ber. 113, 3697-3705, 1980. For the cleavage of the catechol acetals, a more than 13-fold amount of diisobutylaluminum hydride is used in the molar ratio.
A. Gambacorta, D. Tofani, A. Migliorini; Molecules 2007, 12, 1762-1770 describe a three-stage hydroxytyrosol synthesis which starts from methyl 3,4-dihydroxyphenylacetate. The process is complex and methyl 3,4-dihydroxyphenylacetate is not a standard commercial substance and, according to this literature reference, has to itself be prepared in a multistage process.